The Optimal Timing of Stage 2 Palliation for Hypoplastic Left Heart Syndrome: An Analysis of the Pediatric Heart Network Single Ventricle Reconstruction Trial Public Data Set

Abstract

Background: In infants requiring 3-stage single-ventricle palliation for hypoplastic left heart syndrome, attrition after the Norwood procedure remains significant. The effect of the timing of stage 2 palliation (S2P), a physician-modifiable factor, on long-term survival is not well understood. We hypothesized that an optimal interval between the Norwood and S2P that both minimizes pre-S2P attrition and maximizes post-S2P survival exists and is associated with individual patient characteristics.

Methods: The National Institutes of Health/National Heart, Lung, and Blood Institute Pediatric Heart Network Single Ventricle Reconstruction Trial public data set was used. Transplant-free survival (TFS) was modeled from (1) Norwood to S2P and (2) S2P to 3 years by using parametric hazard analysis. Factors associated with death or heart transplantation were determined for each interval. To account for staged procedures, risk-adjusted, 3-year, post-Norwood TFS (the probability of TFS at 3 years given survival to S2P) was calculated using parametric conditional survival analysis. TFS from the Norwood to S2P was first predicted. TFS after S2P to 3 years was then predicted and adjusted for attrition before S2P by multiplying by the estimate of TFS to S2P. The optimal timing of S2P was determined by generating nomograms of risk-adjusted, 3-year, post-Norwood, TFS versus the interval from the Norwood to S2P.

Results: Of 547 included patients, 399 survived to S2P (73%). Of the survivors to S2P, 349 (87%) survived to 3-year follow-up. The median interval from the Norwood to S2P was 5.1 (interquartile range, 4.1-6.0) months. The risk-adjusted, 3-year, TFS was 68±7%. A Norwood-S2P interval of 3 to 6 months was associated with greatest 3-year TFS overall and in patients with few risk factors. In patients with multiple risk factors, TFS was severely compromised, regardless of the timing of S2P and most severely when S2P was performed early. No difference in the optimal timing of S2P existed when stratified by shunt type.

Conclusions: In infants with few risk factors, progressing to S2P at 3 to 6 months after the Norwood procedure was associated with maximal TFS. Early S2P did not rescue patients with greater risk factor burdens. Instead, referral for heart transplantation may offer their best chance at long-term survival.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Keywords: arteriovenous shunt, surgical; heart defects, congenital; statistics; surgery; survival.

Figure 1

Risk-adjusted, transplant-free survival at three years after the Norwood operation in the Single Ventricle Reconstruction Trial. Using the parametric models for transplant-free survival after the Norwood and after S2P, curves representing transplant-free survival were calculated for all 547 patients in the trial, using their actual risk factor values. All curves were then averaged into a single curve, which is displayed here. The risk-adjusted, transplant-free survival at three years was 68±7%. The dashed lines represent the 70% confidence limits.

Figure 2

The optimal timing of Stage-2-Palliation (S2P) in the Single Ventricle Reconstruction Trial. In this nomogram, the probability of transplant-free survival at three years after the Norwood procedure is plotted versus the interval between the Norwood and S2P operations in months (solid line). Calculated transplant-free survival is severely compromised until after three months, at which it stabilizes at 68±7%, and begins to decrease again after six months. This curve was generated by producing nomograms for all 547 patients in the trial and averaging them into a single curve. The dashed lines represent the 70% confidence limits.

Figure 3

A. The optimal timing of Stage-2-Palliation (S2P) stratified by shunt type. No Norwood-S2P is associated with differential calculated, risk-adjusted, transplant-free survival whether the patients had a modified Blalock-Taussig shunt (MBTS) or a right-ventricle-to-pulmonary-artery (RVPA) conduit. This curve was generated by generating nomograms for all 547 patients in the trial, then averaging them into a single curve, and stratifying by shunt type at the end of the Norwood hospitalization. B. The optimal timing of S2P, stratified by the presence of Failure to Thrive (FTT) as an indication for progression to S2P. Performing S2P earlier than six months after the Norwood in patients with FTT is associated with calculated risk-adjusted, transplant-free survival of less than 50%. This curve was generated by producing nomograms for all 547 patients in the trial, then averaging them into a single curve, and stratifying by FTT. The dashed lines represent the 70% confidence limits.

Figure 3

A. The optimal timing of Stage-2-Palliation (S2P) stratified by shunt type. No Norwood-S2P is associated with differential calculated, risk-adjusted, transplant-free survival whether the patients had a modified Blalock-Taussig shunt (MBTS) or a right-ventricle-to-pulmonary-artery (RVPA) conduit. This curve was generated by generating nomograms for all 547 patients in the trial, then averaging them into a single curve, and stratifying by shunt type at the end of the Norwood hospitalization. B. The optimal timing of S2P, stratified by the presence of Failure to Thrive (FTT) as an indication for progression to S2P. Performing S2P earlier than six months after the Norwood in patients with FTT is associated with calculated risk-adjusted, transplant-free survival of less than 50%. This curve was generated by producing nomograms for all 547 patients in the trial, then averaging them into a single curve, and stratifying by FTT. The dashed lines represent the 70% confidence limits.

Figure 4

The optimal timing of Stage-2-Palliation (S2P), stratified by risk profile. In low-risk patients (blue line), the optimal timing of S2P that maximizes calculated risk-adjusted, transplant-free survival at three years after the Norwood does not differ from the cohort average (black line, generated using all 547 patients, averaged into a single curve). In high risk patients (orange line), earlier S2P is associated with much lower calculated risk-adjusted, transplant-free survival, 50% or lower. Risk factor values, patient with few risk factors: Did not require extracorporeal membrane oxygenation (ECMO) at the end of the Norwood procedure, modified Blalock-Taussig shunt, received steroids, pre-Norwood tricuspid valve z-score=4.3, no aberrant right subclavian artery, received aprotinin, site volume < 30 Norwood procedures/year, cardiopulmonary bypass time=111 minutes, highest pre-Norwood lactate=4.0 mg/dL, deep hypothermic circulatory arrest time=0 minutes, post-Norwood neo-aortic annular area z-score=10.85, no pulmonary arterial stenosis, three post-Norwood complications, no diagnosis of failure to thrive, diagnosed with severe atrioventricular valve regurgitation on pre-S2P echocardiogram, did not require ECMO before Norwood hospitalization discharge, and right ventricular ejection fraction=43.9% on the pre-S2P echocardiogram. Risk factor values, patient with multiple risk factors: Did not require extracorporeal membrane oxygenation (ECMO) at the end of the Norwood procedure, Right-Ventricle-to-Pulmonary-Artery conduit, received steroids, pre-Norwood tricuspid valve z-score=0.4, no aberrant right subclavian artery, received aprotinin, site volume < 30 Norwood procedures/year, cardiopulmonary bypass time=140 minutes, highest pre-Norwood lactate=1.9 mg/dL, deep hypothermic circulatory arrest time=60 minutes, post-Norwood neo-aortic annular area z-score=1.63, no pulmonary arterial stenosis, one post-Norwood complication, diagnosed with failure to thrive, no diagnosis of severe atrioventricular valve regurgitation on pre-S2P echocardiogram, did not require ECMO before Norwood hospitalization discharge, and right ventricular ejection fraction=56.2% on pre-S2P echocardiogram.

Figure 5

A. The elective status of the Stage-2-Palliation (S2P) by month after the Norwood procedure in which S2P was performed. B. The outcomes of patients by month after the Norwood procedure in which S2P was performed.